Steroid avoidance or withdrawal for kidney transplant recipients(review)

Transcription

1 Cochrane Database of Systematic Reviews Steroid avoidance or withdrawal for kidney transplant recipients(review) HallerMC,RoyuelaA,NaglerEV,PascualJ,WebsterAC Haller MC, Royuela A, Nagler EV, Pascual J, Webster AC. Steroid avoidance or withdrawal for kidney transplant recipients. Cochrane Database of Systematic Reviews 2016, Issue 8. Art. No.: CD DOI: / CD pub3. Steroid avoidance or withdrawal for kidney transplant recipients(review) Copyright 2016 The Cochrane Collaboration. Published by John Wiley& Sons, Ltd.

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY SUMMARY OF FINDINGS FOR THE MAIN COMPARISON BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure Figure Figure ADDITIONAL SUMMARY OF FINDINGS DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Steroid withdrawal versus steroid maintenance, Outcome 1 Death and graft loss Analysis 1.2. Comparison 1 Steroid withdrawal versus steroid maintenance, Outcome 2 Rejection Analysis 1.3. Comparison 1 Steroid withdrawal versus steroid maintenance, Outcome 3 New-onset diabetes after transplantation and cardiovascular events Analysis 1.4. Comparison 1 Steroid withdrawal versus steroid maintenance, Outcome 4 Infection and malignancy Analysis 1.5. Comparison 1 Steroid withdrawal versus steroid maintenance, Outcome 5 Kidney function Analysis 2.1. Comparison 2 Steroid avoidance versus steroid maintenance, Outcome 1 Death and graft loss Analysis 2.2. Comparison 2 Steroid avoidance versus steroid maintenance, Outcome 2 Rejection Analysis 2.3. Comparison 2 Steroid avoidance versus steroid maintenance, Outcome 3 New-onset diabetes after transplantation and cardiovascular events Analysis 2.4. Comparison 2 Steroid avoidance versus steroid maintenance, Outcome 4 Infection and malignancy Analysis 2.5. Comparison 2 Steroid avoidance versus steroid maintenance, Outcome 5 Kidney function Analysis 3.1. Comparison 3 Steroid avoidance versus steroid withdrawal, Outcome 1 Death and graft loss Analysis 3.2. Comparison 3 Steroid avoidance versus steroid withdrawal, Outcome 2 Rejection Analysis 3.3. Comparison 3 Steroid avoidance versus steroid withdrawal, Outcome 3 New-onset diabetes after transplantation, infection, malignancy Analysis 3.4. Comparison 3 Steroid avoidance versus steroid withdrawal, Outcome 4 Kidney function Analysis 4.1. Comparison 4 Steroid withdrawal versus maintenance in children, Outcome 1 Death and graft loss Analysis 4.2. Comparison 4 Steroid withdrawal versus maintenance in children, Outcome 2 Rejection, malignancy Analysis 4.3. Comparison 4 Steroid withdrawal versus maintenance in children, Outcome 3 Kidney function Analysis 5.1. Comparison 5 Publication bias, Outcome 1 Funnel plots ADDITIONAL TABLES APPENDICES WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT DIFFERENCES BETWEEN PROTOCOL AND REVIEW INDEX TERMS i

3 [Intervention Review] Steroid avoidance or withdrawal for kidney transplant recipients Maria C Haller 1,2,3, Ana Royuela 4,5, Evi V Nagler 3,6, Julio Pascual 7, Angela C Webster 8,9,10 1 Section for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University Vienna, Vienna, Austria. 2 Department for Internal Medicine III, Nephrology & Hypertension Diseases, Transplantation Medicine & Rheumatology, Krankenhaus Elisabethinen Linz, Linz, Austria. 3 European Renal Best Practice (ERBP), guidance issuing body of the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA), Methods Support Team, Ghent University Hospital, Ghent, Belgium. 4 CIBER Epidemiologia y Salud Publica (CIBERESP), Hospital Ramon y Cajal, Madrid, Spain. 5 Clinical Biostatistics Unit, Instituto de Investigación Puerta de Hierro (IDIPHIM), Majadahonda, Spain. 6 Renal Division, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium. 7 Department of Nephrology, Hospital del Mar-IMIM, Barcelona, Spain. 8 Sydney School of Public Health, The University of Sydney, Sydney, Australia. 9 Centre for Transplant and Renal Research, Westmead Millennium Institute, The University of Sydney at Westmead, Westmead, Australia. 10 Cochrane Kidney and Transplant, Centre for Kidney Research, The Children s Hospital at Westmead, Westmead, Australia Contact address: Maria C Haller, Section for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University Vienna, Spitalgasse 23, Vienna, A-1090, Austria. maria.haller@meduniwien.ac.at. Editorial group: Cochrane Kidney and Transplant Group. Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 8, Citation: Haller MC, Royuela A, Nagler EV, Pascual J, Webster AC. Steroid avoidance or withdrawal for kidney transplant recipients. Cochrane Database of Systematic Reviews 2016, Issue 8. Art. No.: CD DOI: / CD pub3. Background A B S T R A C T Steroid-sparing strategies have been attempted in recent decades to avoid morbidity from long-term steroid intake among kidney transplant recipients. Previous systematic reviews of steroid withdrawal after kidney transplantation have shown a significant increase in acute rejection. There are various protocols to withdraw steroids after kidney transplantation and their possible benefits or harms are subject to systematic review. This is an update of a review first published in Objectives To evaluate the benefits and harms of steroid withdrawal or avoidance for kidney transplant recipients. Search methods We searched the Cochrane Kidney and Transplant Specialised Register to 15 February 2016 through contact with the Information Specialist using search terms relevant to this review. Selection criteria All randomised and quasi-randomised controlled trials (RCTs) in which steroids were avoided or withdrawn at any time point after kidney transplantation were included. Data collection and analysis Assessment of risk of bias and data extraction was performed by two authors independently and disagreement resolved by discussion. Statistical analyses were performed using the random-effects model and dichotomous outcomes were reported as relative risk (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals. 1

4 Main results We included 48 studies (224 reports) that involved 7803 randomised participants. Of these, three studies were conducted in children (346 participants). The 2009 review included 30 studies (94 reports, 5949 participants). Risk of bias was assessed as low for sequence generation in 19 studies and allocation concealment in 14 studies. Incomplete outcome data were adequately addressed in 22 studies and 37 were free of selective reporting. The 48 included studies evaluated three different comparisons: steroid avoidance or withdrawal compared with steroid maintenance, and steroid avoidance compared with steroid withdrawal. For the adult studies there was no significant difference in patient mortality either in studies comparing steroid withdrawal versus steroid maintenance (10 studies, 1913 participants, death at one year post transplantation: RR 0.68, 95% CI 0.36 to 1.30) or in studies comparing steroid avoidance versus steroid maintenance (10 studies, 1462 participants, death at one year after transplantation: RR 0.96, 95% CI 0.52 to 1.80). Similarly no significant difference in graft loss was found comparing steroid withdrawal versus steroid maintenance (8 studies, 1817 participants, graft loss excluding death with functioning graft at one year after transplantation: RR 1.17, 95% CI 0.72 to 1.92) and comparing steroid avoidance versus steroid maintenance (7 studies, 1211 participants, graft loss excluding death with functioning graft at one year after transplantation: RR 1.09, 95% CI 0.64 to 1.86). The risk of acute rejection significantly increased in patients treated with steroids for less than 14 days after transplantation (7 studies, 835 participants: RR 1.58, 95% CI 1.08 to 2.30) and in patients who were withdrawn from steroids at a later time point after transplantation (10 studies, 1913 participants, RR 1.77, 95% CI 1.20 to 2.61). There was no evidence to suggest a difference in harmful events, such as infection and malignancy, in adult kidney transplant recipients. The effect of steroid withdrawal in children is unclear. Authors conclusions This updated review increases the evidence that steroid avoidance and withdrawal after kidney transplantation significantly increase the risk of acute rejection. There was no evidence to suggest a difference in patient mortality or graft loss up to five year after transplantation, but long-term consequences of steroid avoidance and withdrawal remain unclear until today, because prospective long-term studies have not been conducted. P L A I N L A N G U A G E S U M M A R Y Steroid avoidance or withdrawal for kidney transplant recipients What is the issue? Each year more than 28,000 kidney transplants are performed globally. Kidney transplantation is the treatment of choice for eligible people who have lost kidney function. Most kidney transplant recipients receive corticosteroids as part of their immunosuppression treatment. Steroids are effective in preventing acute rejection, which is a major problem in the early period after kidney transplantation. However, steroids can also lead to serious side effects when taken long-term. This review looked at two strategies to reduce steroid administration after kidney transplantation: either discontinuing steroids soon after transplantation (within 14 days) or stopping steroid treatment later. What did we do? We searched the literature up to February 2016 and identified 48 studies (7803 patients) that were evaluated in this review. Only three studies included children. This is an update of a review that was last published in What did we find? Our review looked at data relating to 7803 kidney transplant recipients. We assessed the risk of bias in all studies and found that most were unblinded, about half did not report funding sources or how they randomised and allocated study participants. We found that the risk of acute rejection significantly increased with both steroid-reducing treatments among adults who received kidney transplants. There was no little or no difference in the numbers of deaths or loss of transplanted kidneys for both steroidreducing strategies within five years after kidney transplantation. Side effects, such as infection, cancer or diabetes after transplantation did not differ between groups of patients whose steroids were discontinued compared with those who continued to take steroids. The effect of steroid withdrawal in children is unclear. Conclusions 2

5 There was no evidence to suggest a difference in patient mortality or graft loss up to five year after transplantation, but longer-term consequences of steroid avoidance and withdrawal still remain unclear. 3

6 S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation] Steroid withdrawal versus steroid maintenance for kidney transplant recipients Patient or population: kidney transplant recipients Intervention: steroid withdrawal Comparison: steroid maintenance Outcomes Illustrative comparative risks*(95% CI) Relative effect (95% CI) Mortality Follow-up: 1 year Graft loss (excluding death) Follow-up: 1 year Acute rejection Follow-up: 1 year Assumed risk Steroid maintenance 22per per per1000 Corresponding risk Steroid withdrawal 15per1000 (8 to 29) 38per1000 (23 to 62) 268per1000 (182 to 396) RR 0.68 (0.36 to 1.3) RR 1.17 (0.72 to 1.92) RR 1.77 (1.2 to 2.61) No of participants (studies) 1913 (10) low 1, (8) low 2, (10) moderate 1 Quality of the evidence (GRADE) NODAT Follow-up: 5 years 57per per1000 (28 to 69) RR 0.77 (0.49 to 1.21) 1439 (6) low 2,4 CM V infection Follow-up: 5 years 100per per1000 (80 to 137) RR 1.04 (0.8 to 1.36) 1758 (5) low 2,5 * The assumed risk is the baseline risk in the control group treated with steroid maintenance. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; NODAT: new-onset diabetes after transplantation; CMV - cytomegalovirus 4

7 GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. M oderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Lowquality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Most studies were unblinded (9 studies) and did not report details about random sequence generation or allocation concealment or both (8 studies). One study had inappropriate random sequence generation. Four studies were industry sponsored. ITT analysis was unclear in four. 2 Total number of events were fewer than Most studies were unblinded (7 studies) and did not report details about random sequence generation or allocation concealment or both (6 studies). One study had inappropriate random sequence generation. Four studies were industry sponsored. ITT analysis was unclear in two. 4 Most studies were unblinded (5 studies) and did not report details about random sequence generation or allocation concealment or both (5 studies). Three studies were industry sponsored. ITT analysis was unclear in three studies. One study had selective outcome reporting. 5 Most studies were unblinded (4 studies) and did not report details about random sequence generation or allocation concealment or both (4 studies). Three studies were industry sponsored. ITT analysis was unclear in two studies. One study had selective outcome reporting. 5

8 B A C K G R O U N D d prednisolone equivalent) were found to be modest and rarely statistically significantly different from placebo (Da Silva 2006). Description of the condition Patients with end-stage kidney disease (ESKD) have to undergo renal replacement therapy which is available either as dialysis or kidney transplantation. Kidney transplantation is the preferred treatment for eligible patients with ESKD, because it offers a nearly normal life and is associated with better survival and quality of life compared to dialysis treatment. More than 16,000 kidney transplants are currently performed annually in the USA (OPTN/SRTR 2014) and more than 12,000 in Europe (ERA-EDTA 2013). Despite kidney transplants from live donors, organ demand exceeds organ availability worldwide and the number of patients wait listed for kidney transplantation continues to rise (ANZDATA 2012; ERA-EDTA 2013; OPTN/SRTR 2014). Although short-term outcomes of kidney transplantation have continuously improved since the 1980s, long-term results have only marginally improved until today. Death with a functioning graft and chronic allograft nephropathy are the most important causes of graft loss (Pascual 2002). Thus, strategies that prolong patient survival and graft patency have become a priority in kidney transplantation. One of the key factors that influence transplant outcomes is immunosuppression which prohibits progressive immune mediated injury of the allograft. Standard immunosuppressive protocols nowadays consist of an initial induction treatment followed by a maintenance regimen. Immunosuppression is induced by an intensive treatment for the initial days after transplantation either with higher dosages of the immunosuppressive drugs or by adding an additional immunosuppressive agent, such as anti-tcell antibodies or interleukin 2 receptor antibodies. Maintenance immunosuppression usually comprises a combination of three drug groups: calcineurin inhibitors, such as cyclosporin (CsA) or tacrolimus (TAC), anti-proliferative agents, such as azathioprine (AZA) or mycophenolate mofetil (MMF) and corticosteroids, such as prednisolone. Corticosteroids are long known for their anti-inflammatory and immunosuppressive properties and have been used to prevent rejection since the early days of kidney transplantation. Although steroids are effective in preventing acute rejection, chronic steroid use may be an important cause of morbidity and mortality (Opelz 2005). Steroids exhibit a wide range of adverse effects, such as skin fragility, bodyweight gain, osteoporosis and cataracts, can adversely affect important cardiovascular and metabolic risk factors including hypertension, hyperglycaemia and dyslipidaemia and may contribute to an increased risk of infection (Coutinho 2011; Czock 2005; Matas 2005; Patel 2001). A literature review on the safety of low dose glucocorticoid treatment in rheumatoid arthritis suggested that the toxicity of steroids is overestimated, because adverse effects of chronic low dose steroid treatment ( 10 mg/ Description of the intervention With the aim to reduce the adverse effects of long-term corticosteroid therapy, there has been much effort to limit the exposure of kidney transplant recipients to steroids. Lessening exposure to steroids can be achieved by either steroid avoidance or steroid withdrawal. In steroid avoidance, steroids are either avoided completely or withdrawn within the first days after kidney transplantation and steroid withdrawal refers to discontinuation of steroids at a certain time point in the later post-transplant phase. This review evaluated all steroid avoidance or withdrawal strategies in kidney transplant recipients. How the intervention might work Steroids show adverse cardiovascular and metabolic effects and therefore discontinuing steroid treatment may take effect by a decrease in this accelerated cardiovascular risk. However, while steroid avoidance and withdrawal potentially reduces post-transplant atherosclerosis, ischaemic heart disease, post-transplant diabetes and death, it may significantly increase the risk of acute rejection. Acute rejection is associated with late graft loss, especially if rejection episodes are severe, followed by impaired kidney function, occur late and affect arteries (Basadonna 1993; Massy 1996). The new immunosuppressants TAC and MMF have led to important declines in the incidence of acute rejection and may provide a more potent substrate to attempt safe steroid-free immunosuppression or steroid withdrawal. Why it is important to do this review It is important to reduce the cardiovascular risk in kidney transplant recipients, who area population at increased cardiovascular risk, but at the same time it is important to avoid rejection and graft loss. Steroids have been associated with increased cardiovascular risk in kidney transplant recipients, but long-term benefits and harms of steroid discontinuation have not yet been established with controlled long-term data (Knight 2010). Prednisone was perceived as the least effective and least favoured immunosuppressive drug compared to calcineurin inhibitors, MMF and AZA in a survey among Canadian kidney transplant recipients and the majority of US transplant physicians and surgeons stated that steroid-free immunosuppression was a goal for future organ transplant recipients (Hricik 2002; Prasad 2003). Steroid use varies largely in clinical practice around the globe. While steroids are discontinued in many centres worldwide, they are at the same time frequently used for long-term treatment in kidney transplant recipients to protect the allograft. There is no consensus whether 6

9 discontinuation of steroids is safe, what type of patients benefit from steroid discontinuation and at what time point after transplantation steroids are best stopped. A number of RCTs evaluating steroid avoidance or withdrawal at various time-points after kidney transplantation with different immunosuppressive regimes have been performed during the last decades and were first systematically reviewed in 2009 (Pascual 2009). Steroid avoidance and steroid withdrawal strategies in kidney transplantation were not associated with increased patient mortality or graft loss, despite an overall higher incidence of acute rejection for steroid withdrawal strategies compared with steroid maintenance. The aim of this review was to update the benefits and harms of steroid withdrawal and avoidance in kidney transplant recipients with new evidence from RCTs. O B J E C T I V E S To evaluate the benefits and harms of steroid withdrawal or avoidance for kidney transplant recipients. M E T H O D S Criteria for considering studies for this review Types of studies All RCTs or quasi-rcts (in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods), whether published or unpublished, in which steroids were avoided or withdrawn at any time point after kidney transplantation were eligible for inclusion. RCTs evaluating any other steroid-sparing strategy (i.e. dose reduction) or attempting other interventions in addition to steroid withdrawal (i.e. switch from AZA to MMF, induction treatment in addition to steroid withdrawal) were excluded in this review. Types of participants Adult and paediatric recipients of a first or subsequent kidney transplant from a cadaveric or living donor. Recipients of multiorgan transplants (kidney-pancreas, kidney-liver, kidney-heart) were excluded. Types of interventions Steroid avoidance, defined as steroid use during less than 14 days after kidney transplantation versus steroid maintenance Steroid withdrawal, defined as steroid use for more than 14 days after transplantation versus steroid maintenance Steroid avoidance versus steroid withdrawal. Types of outcome measures Outcome measures used by transplant registries to report patient and graft survival were selected for this review. Outcome events were assessed within the first year and up to five years after kidney transplantation. A secondary outcome looking at infection has been amended for this update to specify cytomegalovirus (CMV) infection. Primary outcomes 1. All-cause mortality 2. Graft loss or death with a functioning graft; and graft loss censored for death with a functioning graft (loss of graft function resulting in either return to dialysis or retransplantation) 3. Acute rejection (clinically suspected and treated) and biopsy-proven acute rejection. Secondary outcomes 1. Cardiovascular events 2. New-onset diabetes after transplantation (NODAT) 3. Malignancy 4. Infection and CMV infection 5. Kidney function measures (serum creatinine (mg/dl); creatinine clearance (ml/min)). Search methods for identification of studies Electronic searches We searched the Cochrane Kidney and Transplant Specialised Register up to 15 February 2016 through contact with the Information Specialist using search terms relevant to this review. The Specialised Register contains studies identified from several sources. 1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL) 2. Weekly searches of MEDLINE OVID SP 3. Handsearching of kidney-related journals and the proceedings of major kidney conferences 4. Searching of the current year of EMBASE OVID SP 5. Weekly current awareness alerts for selected kidney journals 6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of these strategies, as well as a list of handsearched journals, conference 7

10 proceedings and current awareness alerts, are available in the Specialised Register section of information about Cochrane Kidney and Transplant. See Appendix 1 for search terms used in strategies for this review. Searching other resources 1. Reference lists of review articles, relevant studies and clinical practice guidelines. 2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies. Data collection and analysis Selection of studies The search strategies described was used to obtain title and abstracts of studies relevant to this review. Three authors independently screened titles and abstracts, and discarded reports that were not applicable. Studies and reviews that might include relevant data or information on studies were retained initially and two authors independently assessed retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfied the inclusion criteria. Disagreement about inclusion was resolved by discussion with a third author. Data extraction and management Two authors independently carried out data extraction using standard data extraction forms. Studies reported in non-english language journals will be translated before assessment. Where more than one report of a study existed, reports were grouped together and the publication with the most complete data was used in the analyses. We examined any prior or subsequent report for supplementary outcomes or data to ensure the inclusion of all relevant information. If data were unclear, ambiguous or missing, authors were contacted for further information and any provided additional data was included in the review. Whenever necessary, disagreements were resolved by discussion. Assessment of risk of bias in included studies Two authors independently assessed the following items using the risk of bias assessment tool (Higgins 2011) (see Appendix 2). Was there adequate sequence generation (selection? Was allocation adequately concealed (selection? Was knowledge of the allocated interventions adequately prevented during the study? Participants and personnel (performance Outcome assessors (detection Were incomplete outcome data adequately addressed (attrition? Are reports of the study free of suggestion of selective outcome reporting (reporting? Was the study apparently free of other problems that could put it at a risk of bias? Measures of treatment effect For dichotomous outcomes results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment, the mean difference (MD) was used, or the standardised mean difference (SMD) if different scales had been used. Unit of analysis issues The unit of analysis was the study participant and not the events; that is the number of study participants with an acute rejection rather than the number of episodes of acute rejection. Dealing with missing data Any further information required from the original author was requested by written correspondence (e.g. ing corresponding author) and any relevant information obtained in this manner was to be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention-totreat, as-treated and per-protocol population will be carefully performed. Attrition rates, for example drop-outs, losses to follow-up and withdrawals were investigated. Issues of missing data and imputation methods (for example, last-observation-carried-forward) were critically appraised (Higgins 2011). If standard deviation was not available, it was estimated using standard error (if provided) (Higgins 2011). Assessment of heterogeneity Heterogeneity was analysed using a Chi 2 (on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance) and with the I 2 statistic, calculated to measure the proportion of total variation in the estimates of treatment effect that was due to heterogeneity beyond chance (Higgins 2003). I 2 values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity. Assessment of reporting biases We assessed publication bias by constructing funnel plots for primary outcomes if there was sufficient data available to enable this analysis (at least 10 included studies in the meta-analysis). 8

11 Data synthesis Data were pooled for summary estimates using the random-effects model but the fixed-effect model was also to be used to ensure robustness of the model chosen and susceptibility to outliers. Results reported used the random-effects model because this is more conservative in the presence of known or unknown heterogeneity (Deeks 2001). R E S U L T S Description of studies Subgroup analysis and investigation of heterogeneity Subgroup analyses were used to explore possible sources of heterogeneity and potential effect modifiers were defined a priori. The main source of heterogeneity among participants could be related to age, therefore adults and children who were kidney transplant recipients were analysed separately. Heterogeneity in treatments could be related to duration of steroid therapy and concomitant immunosuppressants. Therefore subgroup analysis was undertaken using stratified meta-analysis for type of calcineurin inhibitor, type of antimetabolite and whether an induction treatment was administered. Sensitivity analysis Sensitivity analysis was performed to demonstrate that final results did not vary where low quality studies were included or excluded. Low quality studies were defined based on publication type (conference abstract or peer reviewed journal) and methodological conduct (whether intention-to-treat analysis was assessed as adequate or inadequate/unclear). Results of the search A search in 15 February 2016 identified 151 reports. Additionally three previously excluded studies were re-evaluated and included; these had been incorrectly excluded for reasons of insufficient data (Aswad 1998; Kacar 2004; Pisani 2001). All three are published as abstract only. Pisani 2001 contributed data for the meta-analysis. We also re-evaluated three previously included studies and excluded them because they had been incorrectly included despite a wrong co-intervention (CARMEN Study 2005; Tarantino 1991; ter Meulen 2002). In CARMEN Study 2005 and ter Meulen 2002 induction treatment with daclizumab was only given to patients in the steroid withdrawal group and in Tarantino 1991 AZA was given solely to patients in the steroid maintenance group. We included 21 new studies (59 reports) that involved 1854 participants, two of these new studies (seven reports) concerned children. We found that 88 new reports were additional reports of previously included studies. This update includes 48 studies (224 reports) that involved 7803 participants, including three studies (11 reports) that involved 346 children. See Figure 1. 9

12 Figure 1. Study flow diagram. Included studies See Characteristics of included studies. The 48 included studies were published in 22 different journals and seven had preliminary abstract data only available (Aswad 1998; Burke 2000; del Castillo 2005; INFINITY Study 2013; Kacar 2004; Kim 2002; Pisani 2001).The effect of steroid withdrawal compared versus steroid maintenance was investigated in 26 studies (4022 participants) and the effect of steroid avoidance compared versus steroid maintenance was investigated in 19 studies (3401 participants). We identified three studies (380 participants) that evaluated the effect of steroid avoidance compared versus steroid withdrawal. Numbers of participants per study varied from 21 (Aswad 1998) to 560 patients (THOMAS Study 2002). It is noteworthy that 25 studies randomised fewer than 100 participants, 15 studies included between 100 and 300 participants, and eight studies randomised more than 300 participants. Trials in adult kidney transplant recipients This update included 45 studies (208 reports, 7457 participants) of steroid withdrawal or avoidance in adult kidney transplant re- 10

13 cipients. Participants Trials recruited participants who were older than 18 years of age, except two studies which recruited participants older than 12 years (Stiller 1983) or between five and 62 years (Nagib 2015). In 14 studies the age range was not further specified (Albert 1985; Aswad 1998; Gulanikar 1991; INFINITY Study 2013; Isoniemi 1990; Johnson 1989a; Kacar 2004; Kim 2002; Ratcliffe 1993; Schulak 1989; Smak Gregoor 1999; Sola 2002; THOMAS Study 2002; Zhu 2008a).The majority of studies included cadaveric and living kidney transplant recipients (25 studies: Ahsan 1999; ATLAS Study 2005; Boletis 2001; Boots 2002; Burke 2000; DOMINOS Study 2012; EVIDENCE Study 2014; Farmer 2006; FREEDOM Study 2008; Gulanikar 1991; Jankowska-Gan 2009; Kim 2002; Kumar 2005; Laftavi 2005; Lebranchu 1999; Matl 2000; Montagnino 2005; Nott 1985; Pelletier 2006; Schulak 1989; Stiller 1983; Smak Gregoor 1999; THOMAS Study 2002; Vincenti 2003a; Woodle 2005). Kidney transplantation was limited to cadaveric donor sources in 11 studies (Bouma 1996; De Vecchi 1986; FRANCIA Study 2007; Isoniemi 1990; Johnson 1989a; Maiorca 1988; Ponticelli 1997; Ratcliffe 1993; Sandrini 2009; Sola 2002; Zhu 2008a) and to living donors in four studies (Aswad 1998; Nagib 2015; Nematalla 2007; Park 1994) In 17 studies first or subsequent kidney transplant recipients were eligible (Boots 2002; Bouma 1996; DOMINOS Study 2012; EVIDENCE Study 2014; Farmer 2006; Gulanikar 1991; Johnson 1989a; Lebranchu 1999; Montagnino 2005; Nott 1985; Pisani 2001; Ponticelli 1997; Ratcliffe 1993; Schulak 1989; Stiller 1983; THOMAS Study 2002; Woodle 2005), while in 19 studies limited participants to recipients of first kidney transplants (Ahsan 1999; ATLAS Study 2005; Boletis 2001; Burke 2000; del Castillo 2005; FRANCIA Study 2007; FREEDOM Study 2008; INFINITY Study 2013; Isoniemi 1990; Kumar 2005; Laftavi 2005; Maiorca 1988; Matl 2000; Nagib 2015; Nematalla 2007; Park 1994; Pelletier 2006; Sandrini 2009; Vincenti 2003a). Study comparisons The 45 included studies evaluated three different comparisons in adults. Steroid withdrawal compared versus steroid maintenance was investigated in 24/45 studies in adult patients (Ahsan 1999; Albert 1985; Aswad 1998; Boletis 2001; Bouma 1996; Burke 2000; del Castillo 2005; EVIDENCE Study 2014; Farmer 2006; Gulanikar 1991; Isoniemi 1990; Jankowska-Gan 2009; Kacar 2004; Lebranchu 1999; Maiorca 1988; Matl 2000; Park 1994; Pelletier 2006; Pisani 2001; Ratcliffe 1993; Smak Gregoor 1999; Sola 2002; THOMAS Study 2002; Zhu 2008a). Steroids were withdrawn three months after transplantation in eight studies (Ahsan 1999; EVIDENCE Study 2014; Gulanikar 1991; Isoniemi 1990; Lebranchu 1999; Park 1994; Sola 2002; THOMAS Study 2002); six months after transplantation in eight studies (Albert 1985; Aswad 1998; Boletis 2001; Burke 2000; del Castillo 2005; Pisani 2001; Smak Gregoor 1999; Zhu 2008a); one year after transplantation in one study (Matl 2000), and beyond one year after transplantation in six studies (Bouma 1996; Farmer 2006; Jankowska-Gan 2009; Kacar 2004; Maiorca 1988; Ratcliffe 1993). In one study, steroids were withdrawn at different time points after transplantation and the time point of withdrawal was not reported, but all patients had steroids for more than 14 days (Pelletier 2006). Steroid avoidance compared versus steroid maintenance was investigated in 18/45 studies in adult kidney transplant recipients (ATLAS Study 2005; De Vecchi 1986; FRANCIA Study 2007; FREEDOM Study 2008; Nott 1985; INFINITY Study 2013; Johnson 1989a; Kim 2002; Kumar 2005; Laftavi 2005; Stiller 1983; Montagnino 2005; Nagib 2015; Nematalla 2007; Ponticelli 1997; Schulak 1989; Vincenti 2003a; Woodle 2005). In two studies steroids were not given at any time point before, during or after transplantation (FREEDOM Study 2008; Stiller 1983). Steroids were withdrawn until day seven after transplantation in 12 studies (ATLAS Study 2005; De Vecchi 1986; FRANCIA Study 2007; Nott 1985; Johnson 1989a; Kim 2002; Kumar 2005; Laftavi 2005; Montagnino 2005; Nematalla 2007; Ponticelli 1997; Vincenti 2003a) and between day 8 and day 14 in two studies (Schulak 1989; Woodle 2005). Steroid avoidance was compared versus steroid withdrawal in 3/45 studies with adults (Boots 2002; DOMINOS Study 2012; Sandrini 2009). In all of these three studies, steroids were withdrawn until day seven after transplantation in the avoidance group and between three to six months after transplantation in the withdrawal group. Immunosuppression CsA was used in 34 studies evaluating steroid withdrawal or steroid avoidance (Ahsan 1999; Albert 1985; Boletis 2001; Bouma 1996; Burke 2000; del Castillo 2005; De Vecchi 1986; DOMINOS Study 2012; EVIDENCE Study 2014; Farmer 2006; FRANCIA Study 2007; FREEDOM Study 2008; Gulanikar 1991; INFINITY Study 2013; Isoniemi 1990; Jankowska-Gan 2009; Johnson 1989a; Kim 2002; Kumar 2005; Lebranchu 1999; Maiorca 1988; Matl 2000; Montagnino 2005; Nott 1985; Park 1994; Pelletier 2006; Pisani 2001; Ponticelli 1997; Ratcliffe 1993; Sandrini 2009; Schulak 1989; Smak Gregoor 1999; Vincenti 2003a). TAC was used in 10 studies investigating steroid withdrawal or steroid avoidance (Aswad 1998; ATLAS Study 2005; Boots 2002; Laftavi 2005; Nagib 2015; Nematalla 2007; Sola 2002; THOMAS Study 2002; Woodle 2005; Zhu 2008a). One study provided no information about the baseline immunosuppression used (Kacar 2004). Of the three studies comparing steroid avoidance with steroid withdrawal, two used a CsA-based im- 11

14 munosuppression (DOMINOS Study 2012; Sandrini 2009) and one used a TAC-based immunosuppression (Boots 2002). Five studies investigated steroid withdrawal compared versus steroid maintenance in patients without an additional antiproliferative immunosuppressant (either MMF or enteric-coated mycophenolate sodium or AZA or mtor-inhibitor) (Albert 1985; Bouma 1996; Gulanikar 1991; Maiorca 1988; Park 1994) and five studies investigated steroid avoidance compared versus steroid maintenance without an additional antiproliferative (De Vecchi 1986; Johnson 1989a; Nott 1985; Stiller 1983; Ponticelli 1997). Steroid avoidance compared versus steroid withdrawal in patients without an antiproliferative was investigated in Boots An immunosuppressive regimen including an additional antiproliferative agent was used in 18 studies that investigated steroid withdrawal compared versus steroid maintenance (Ahsan 1999; Aswad 1998; Boletis 2001; Burke 2000; del Castillo 2005; EVIDENCE Study 2014; Farmer 2006; Isoniemi 1990; Jankowska-Gan 2009; Lebranchu 1999; Matl 2000; Pelletier 2006; Pisani 2001; Ratcliffe 1993; Smak Gregoor 1999; Sola 2002; THOMAS Study 2002; Zhu 2008a). Of these 18 studies, 12 used MMF (Ahsan 1999; Boletis 2001; del Castillo 2005; Burke 2000; Jankowska-Gan 2009; Pelletier 2006; Pisani 2001; Smak Gregoor 1999; Sola 2002; THOMAS Study 2002; Lebranchu 1999; Zhu 2008a), five used AZA (Aswad 1998; Farmer 2006; Isoniemi 1990; Matl 2000; Ratcliffe 1993), and one used Everolimus (EVIDENCE Study 2014). Steroid avoidance compared versus steroid maintenance using an additional antiproliferative immunosuppressant was used in 13 studies (ATLAS Study 2005; FRANCIA Study 2007; FREEDOM Study 2008; INFINITY Study 2013; Kim 2002; Kumar 2005; Laftavi 2005; Montagnino 2005; Nagib 2015; Nematalla 2007; Schulak 1989; Vincenti 2003a; Woodle 2005). Of these, nine used MMF (ATLAS Study 2005; FRANCIA Study 2007; Kim 2002; Kumar 2005; Laftavi 2005; Nagib 2015 Nematalla 2007; Vincenti 2003a; Woodle 2005), two used enteric-coated mycophenolate sodium (FREEDOM Study 2008; INFINITY Study 2013), one used AZA (Schulak 1989), and one used everolimus (Montagnino 2005). Steroid avoidance compared versus steroid withdrawal in patients treated with an additional antiproliferative was investigated in two studies (DOMINOS Study 2012; Sandrini 2009). One study used enteric-coated mycophenolate sodium (DOMINOS Study 2012) and one used sirolimus (Sandrini 2009) as the third immunosuppressant. Induction treatment was administered in 17 studies with adult kidney transplant recipients in three studies comparing steroid withdrawal with steroid maintenance (EVIDENCE Study 2014; Pelletier 2006; Pisani 2001), in 12 studies comparing steroid avoidance with steroid maintenance (FRANCIA Study 2007; FREEDOM Study 2008; INFINITY Study 2013; Kim 2002; Kumar 2005; Laftavi 2005; Montagnino 2005; Nagib 2015; Nematalla 2007; Schulak 1989; Vincenti 2003a; Woodle 2005), and in two studies comparing steroid avoidance with steroid withdrawal (DOMINOS Study 2012; Sandrini 2009). In 12 studies an IL-2 receptor antagonist was used for induction treatment (DOMINOS Study 2012; EVIDENCE Study 2014; FREEDOM Study 2008; INFINITY Study 2013; Kim 2002; Kumar 2005; Montagnino 2005; Nagib 2015; Nematalla 2007; Pisani 2001; Sandrini 2009; Vincenti 2003a), in three studies an anti-lymphocytic depleting antibodies was used (FRANCIA Study 2007; Laftavi 2005; Schulak 1989) and two studies allowed the type of induction treatment to be chosen by the investigator (Pelletier 2006; Woodle 2005). Studies in child kidney transplant recipients This update included three studies (11 reports, 346 participants) of steroid withdrawal or avoidance in child kidney transplant recipients (Benfield 2005; Höcker 2009; Mericq 2013). Participants Studies recruited participants who were younger than 20 years of age. All three studies included cadaveric and living kidney transplant recipients. In Benfield 2005 and Mericq 2013 only first kidney transplant recipients were eligible; in Höcker 2009 first or subsequent kidney transplantation was included. Study comparisons The three studies evaluated two different comparisons in children. Benfield 2005 and Höcker 2009 investigated steroid withdrawal versus steroid maintenance; Mericq 2013 investigated steroid avoidance versus steroid withdrawal. Immunosuppression All three studies used a calcineurin inhibitor-based immunosuppressive regimen including an additional antiproliferative agent. Höcker 2009 used CsA and MMF, Benfield 2005 allowed either CsA or TAC to be used with sirolimus and Mericq 2013 used TAC in combination with MMF. Benfield 2005 and Mericq 2013 also used basiliximab for induction treatment, but Benfield 2005 was terminated early when the Data Safety Monitoring Board noted an excess risk of post-transplant lymphoproliferative disease in both treatment groups. Reported outcome measures The reporting of outcome measures varied across studies. Of the 45 included studies, 34 reported patient mortality and 23 reported acute rejection (see Figure 1). Reporting of harms was more limited and inconsistent among studies (six studies reported cardiovascular events with varying definitions of cardiovascular events or definitions not reported). Frequently, studies reported incomplete data for harm outcomes or expressed their results as episodes, 12

15 which complicated meaningful use of such data in the meta-analysis. Excluded studies We excluded a total of 48 studies because studies: were not randomised (12), concerned ineligible populations (3), involved ineligible interventions ( 11) or ineligible co-interventions (22). Risk of bias in included studies Reporting of details of study methodology regarding design and conduct of the study was incomplete in most studies. The assessment of risk of bias is shown in Figure 2 and Figure 3. Figure 2 shows the risk of bias indicators for individual studies. Figure 3 shows the proportion of studies assessed as low, high or unclear risk of bias for each risk of bias indicator. 13

16 Figure 2. Risk of bias summary: review authors judgements about each risk of bias item for each included study 14

17 Figure 3. Risk of bias graph: review authors judgements about each risk of bias item presented as percentages across all included studies Allocation Random sequence generation was judged to be at low risk of bias in 19 studies (Ahsan 1999; ATLAS Study 2005; Benfield 2005; DOMINOS Study 2012; EVIDENCE Study 2014; FRANCIA Study 2007; FREEDOM Study 2008; Gulanikar 1991; Höcker 2009; Johnson 1989a; Kumar 2005; Laftavi 2005; Mericq 2013; Montagnino 2005; Nematalla 2007; Ponticelli 1997; Schulak 1989; Stiller 1983; Woodle 2005) and considered at high risk in two studies (Aswad 1998; Matl 2000). Randomisation methods were not reported in 27 studies (Albert 1985; Boletis 2001; Boots 2002; Bouma 1996; Burke 2000; del Castillo 2005; De Vecchi 1986; Farmer 2006; INFINITY Study 2013; Isoniemi 1990; Jankowska-Gan 2009; Kacar 2004; Kim 2002; Lebranchu 1999; Maiorca 1988; Nagib 2015; Nott 1985; Park 1994; Pelletier 2006; Pisani 2001; Ratcliffe 1993; Sandrini 2009; Smak Gregoor 1999; Sola 2002; THOMAS Study 2002; Vincenti 2003a; Zhu 2008a). Allocation concealment was assessed to be at low risk of bias in 14 studies (ATLAS Study 2005; Boots 2002; De Vecchi 1986; DOMINOS Study 2012; Farmer 2006; FRANCIA Study 2007; Gulanikar 1991; Isoniemi 1990; Mericq 2013; Montagnino 2005; Nematalla 2007; Smak Gregoor 1999; Stiller 1983; Woodle 2005); no study was judged to be at high risk of bias. Methods used for allocation concealment were unclear in the remaining 34 studies (Ahsan 1999; Albert 1985; Aswad 1998; Benfield 2005; Boletis 2001; Bouma 1996; Burke 2000; del Castillo 2005; EVIDENCE Study 2014; FREEDOM Study 2008; Höcker 2009; INFINITY Study 2013; Jankowska-Gan 2009; Johnson 1989a; Kacar 2004; Kim 2002; Kumar 2005; Laftavi 2005; Lebranchu 1999; Maiorca 1988; Matl 2000; Nagib 2015; Nott 1985; Park 1994; Pelletier 2006; Pisani 2001; Ponticelli 1997; Ratcliffe 1993; Sandrini 2009; Schulak 1989; Sola 2002; THOMAS Study 2002; Vincenti 2003a; Zhu 2008a). Blinding Participants and investigators were blinded in only five studies ( Ahsan 1999; Benfield 2005; Burke 2000; Gulanikar 1991; Woodle 2005). The absence of blinding was judged as high risk of bias because clinical management could be influenced by knowledge of treatment group. Blinding of outcome assessment was considered as low risk of bias because outcomes were objective and therefore more robust against influence by knowledge of treatment group (e.g. death, graft loss, serum creatinine). Incomplete outcome data Incomplete outcome data was judged to be at low risk of bias in 22 studies (Ahsan 1999; ATLAS Study 2005; Benfield 2005; Boots 2002; Bouma 1996; del Castillo 2005; DOMINOS Study 2012; 15

18 FRANCIA Study 2007; FREEDOM Study 2008; Gulanikar 1991; Höcker 2009; Isoniemi 1990; Kumar 2005; Matl 2000; Montagnino 2005; Ponticelli 1997; Ratcliffe 1993; Schulak 1989; Smak Gregoor 1999; THOMAS Study 2002; Vincenti 2003a; Woodle 2005). Exclusion of participants after randomisation and attrition were considered at high risk in four studies (Boletis 2001; Burke 2000; De Vecchi 1986; Nagib 2015). Methods for addressing incomplete outcome data remained unclear in 22 studies (Albert 1985; Aswad 1998; EVIDENCE Study 2014; Farmer 2006; INFINITY Study 2013; Jankowska-Gan 2009; Johnson 1989a; Kacar 2004; Kim 2002; Laftavi 2005; Lebranchu 1999; Maiorca 1988; Mericq 2013; Nematalla 2007; Nott 1985; Park 1994; Pelletier 2006; Pisani 2001; Sandrini 2009; Sola 2002; Stiller 1983; Zhu 2008a). Selective reporting Selective outcome reporting was judged as low risk in 37 studies (Ahsan 1999; Aswad 1998; ATLAS Study 2005; Benfield 2005; Boots 2002; Bouma 1996; del Castillo 2005; De Vecchi 1986; DOMINOS Study 2012; EVIDENCE Study 2014; FRANCIA Study 2007; FREEDOM Study 2008; Höcker 2009; INFINITY Study 2013; Isoniemi 1990; Jankowska-Gan 2009; Kacar 2004; Kumar 2005; Lebranchu 1999; Maiorca 1988; Matl 2000; Mericq 2013; Montagnino 2005; Nagib 2015; Nematalla 2007; Park 1994; Pelletier 2006; Pisani 2001; Ponticelli 1997; Sandrini 2009; Schulak 1989; Smak Gregoor 1999; Sola 2002; Stiller 1983; THOMAS Study 2002; Vincenti 2003a; Woodle 2005). Eleven studies did not report all hard clinical outcomes that were considered primary outcomes for this review and were assessed as high risk of bias for selective outcome reporting (Albert 1985; Boletis 2001; Burke 2000; Farmer 2006; Gulanikar 1991; Nott 1985; Johnson 1989a; Kim 2002; Laftavi 2005; Ratcliffe 1993; Zhu 2008a). Other potential sources of bias Funding from academic independent sources was considered as low risk of bias in four studies (De Vecchi 1986; Isoniemi 1990; Matl 2000; Mericq 2013). In 16 studies a pharmaceutical company was reported as funding source, which was judged as high risk of bias (Ahsan 1999; ATLAS Study 2005; Benfield 2005; Bouma 1996; DOMINOS Study 2012; FRANCIA Study 2007; FREEDOM Study 2008; Kumar 2005; Montagnino 2005; Gulanikar 1991; Smak Gregoor 1999; Stiller 1983; THOMAS Study 2002; Vincenti 2003a). In 27 studies funding sources were not disclosed (Albert 1985; Aswad 1998; Boletis 2001; Boots 2002; Burke 2000; del Castillo 2005; EVIDENCE Study 2014; Farmer 2006; Höcker 2009; INFINITY Study 2013; Jankowska-Gan 2009; Johnson 1989a; Kacar 2004; Kim 2002; Laftavi 2005; Lebranchu 1999; Maiorca 1988; Nematalla 2007; Nott 1985; Park 1994; Pelletier 2006; Pisani 2001; Ponticelli 1997; Ratcliffe 1993; Sandrini 2009; Schulak 1989; Sola 2002; Woodle 2005; Zhu 2008a). Publication bias was assessed by constructing funnel plots for three comparisons that included at least 10 studies in the meta-analysis (death and acute rejection for steroid withdrawal versus steroid maintenance and acute rejection for steroid avoidance versus steroid maintenance). All funnel plots are symmetric and do not indicate publication bias (see Figure 4). 16